The tumor suppressor miR-642a-5p targets Wilms Tumor 1 gene and cell-cycle progression in prostate cancer

Dianne J Beveridge; Kirsty L Richardson; Michael R Epis; Rikki A M Brown; Lisa M Stuart; Andrew J Woo; Peter J Leedman

doi:10.1038/s41598-021-97190-x

The tumor suppressor miR-642a-5p targets Wilms Tumor 1 gene and cell-cycle progression in prostate cancer

Sci Rep. 2021 Sep 9;11(1):18003. doi: 10.1038/s41598-021-97190-x.

Authors

Dianne J Beveridge^#^{1

2}, Kirsty L Richardson^#^{1

2}, Michael R Epis^#^{1

2}, Rikki A M Brown^{1

2}, Lisa M Stuart^{1

2}, Andrew J Woo^{1

2

3}, Peter J Leedman^{4

5

6}

Affiliations

¹ Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, 6009, Australia.
² Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia.
³ School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, 6027, Australia.
⁴ Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands, 6009, Australia. [email protected].
⁵ Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia. [email protected].
⁶ School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, 6009, Australia. [email protected].

^# Contributed equally.

Abstract

RNA-based therapeutics are emerging as innovative options for cancer treatment, with microRNAs being attractive targets for therapy development. We previously implicated microRNA-642a-5p (miR-642a-5p) as a tumor suppressor in prostate cancer (PCa), and here we characterize its mode of action, using 22Rv1 PCa cells. In an in vivo xenograft tumor model, miR-642a-5p induced a significant decrease in tumor growth, compared to negative control. Using RNA-Sequencing, we identified gene targets of miR-642a-5p which were enriched for gene sets controlling cell cycle; downregulated genes included Wilms Tumor 1 gene (WT1), NUAK1, RASSF3 and SKP2; and upregulated genes included IGFBP3 and GPS2. Analysis of PCa patient datasets showed a higher expression of WT1, NUAK1, RASSF3 and SKP2; and a lower expression of GPS2 and IGFBP3 in PCa tissue compared to non-malignant prostate tissue. We confirmed the prostatic oncogene WT1, as a direct target of miR-642a-5p, and treatment of 22Rv1 and LNCaP PCa cells with WT1 siRNA or a small molecule inhibitor of WT1 reduced cell proliferation. Taken together, these data provide insight into the molecular mechanisms by which miR-642a-5p acts as a tumor suppressor in PCa, an effect partially mediated by regulating genes involved in cell cycle control; and restoration of miR-642-5p in PCa could represent a novel therapeutic approach.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Base Pairing
Base Sequence
Cell Cycle / genetics*
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Neoplastic
Humans
Insulin-Like Growth Factor Binding Protein 3 / genetics
Insulin-Like Growth Factor Binding Protein 3 / metabolism
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Male
Mice
Mice, SCID
MicroRNAs / genetics*
MicroRNAs / metabolism
Monomeric GTP-Binding Proteins / genetics
Monomeric GTP-Binding Proteins / metabolism
Prostate / metabolism*
Prostate / pathology
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / mortality
Prostatic Neoplasms / pathology
Protein Kinases / genetics
Protein Kinases / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
S-Phase Kinase-Associated Proteins / genetics
S-Phase Kinase-Associated Proteins / metabolism
Signal Transduction
Survival Analysis
Tumor Burden
WT1 Proteins / antagonists & inhibitors
WT1 Proteins / genetics*
WT1 Proteins / metabolism
Xenograft Model Antitumor Assays

Substances

3' Untranslated Regions
GPS2 protein, human
IGFBP3 protein, human
Insulin-Like Growth Factor Binding Protein 3
Intracellular Signaling Peptides and Proteins
MIRN642 microRNA, human
MicroRNAs
RASSF3 protein, human
RNA, Small Interfering
Repressor Proteins
S-Phase Kinase-Associated Proteins
WT1 Proteins
WT1 protein, human
Protein Kinases
NUAK1 protein, human
Monomeric GTP-Binding Proteins